Engineered Nanomedicine with Alendronic Acid Corona Improves Targeting to Osteosarcoma

Citation: Nguyen, T. D. T., Pitchaimani, A., & Aryal, S. (2016). Engineered Nanomedicine with Alendronic Acid Corona Improves Targeting to Osteosarcoma. Scientific Reports, 6, 36707.We engineered nanomedicine with the stealth corona made up of densely packed bone seeking ligand, alendronic acid. In a typical nanoconstruct, alendronic acid is conjugated with hydrophilic head moiety of phospholipid that has an ability to self-assemble with hydrophobic polymeric core through its hydrophobic long carbon-chain. Proposed nanomedicine has three distinct compartments namely; poly(l-lactic-co-glycolic acid) polymeric core acting as a drug reservoir and skeleton of the nanoconstruct, phospholipid monolayer covers the core acting as a diffusion barrier, and a densely packed alendronic acid corona acting as a stabilizer and targeting moiety. Thus engineered nanomedicine attain spherical entity with ~90 ± 6 nm having negative zeta potential, −37.7 ± 2 mV, and has an ability to load 7 ± 0.3 wt% of doxorubicin. In-vitro bone targeting efficiency of nanomedicine was studied using hydroxyapatite crystals as a bone model, and found significant accumulation of nanoparticle in the crystals. Moreover, cellular internalization studies with mouse osteosarcoma confirm the selectivity of nanomedicine when compared to its internalization in non-targeted mouse melanoma. This nanomedicine shows prolong stability in serum and deliver the drug into the cell exhibiting an IC50 of 3.7 μM. Given the strong interacting property of alendronic acid with bone, the proposed nanomedicine hold promises in delivering drug to bone microenvironment

Antilarval substituted phenols, distribution of tricyclic pyrones in mice, and synthesis of unnatural amino acids

Doctor of PhilosophyDepartment of ChemistryDuy H. HuaThree research projects were carried out and they are described below. The synthesis of substituted phenolic compounds including halogenated di- and trihydroxybenzenes, aminophenols, and substituted di-tert-butylphenols are described. Redox potentials of the synthesized molecules along with various known laccase substrates were measured, and an inverse relationship between the oxidation potential and the efficiency of oxidation by laccase of halogenated hydroxybenzenes and aminophenols is demonstrated. The synthesized substituted phenols were found to be substrates but not inhibitors of laccase. We discovered a new class of di-tert-butylphenols compounds that inhibits the growth of mosquito larvae at low concentrations. Compound 17, 2,4-di-tert-butyl-6-(3-methyl-2-butenyl) phenol caused greater than 98% mortality of third-instar larvae of Anopheles gambiae in the concentration of 0.18 µM. These compounds do not inhibit laccases. It appears that they affect a new target of the mosquito that is different from those of currently existing pesticides. Two anti-Alzheimer molecules, CP2 and TP70, discovered in our laboratory were studied for their pharmacokinetics and distribution. The distribution of CP2 and TP70 in mouse brain region and various tissues of mice were examined. HPLC analysis revealed that CP2 treatment in primary neurons accumulates in mitochondria fraction. Similarly, the amount of CP2 in the brain tissue from wild type and APP/PS1 mice treated with 25 mg/kg/daily for 2 months also have the highest concentration in the mitochondria fractions in the hippocampus. The results show that CP2 and TP70 can penetrate the blood brain barrier and accumulate in the tissue in significant amounts. Pharmacokinetics and bioavailability of compound TP70 were determined. Area under the curve and bioavailability value F were calculated, and data show that TP70 has a good PK profile and bioavailability. For the preparation of a novel tripeptidyl norovirus 3C-like protease (3CL[superscript]pro) inhibitor, the P3 unnatural amino acid, (S)-3-hydroxyphenylalanine was synthesized. The P3 is designed to increase the polarity with the addition of the alcohol group. After combining the P3 unnatural amino acid with the P1 and P2 to form the novel tripeptidyl compound, a study comparing the relations between the structure and its activity (SAR) will confirm whether prediction is correct in our pursuit for an antiviral therapeutic drug in the form of a protease inhibitor

Synthesis and anti-norovirus activity of pyranobenzopyrone compounds

During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10–100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED[subscript]5[subscript]0 values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4-quinolylmethyl derivative 4A showed ED[subscript]5[subscript]0 values of 3.4 and 2.4 [mu]M and TD[subscript]5[subscript]0 values of >200 and 96.4 [mu]M, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents

Syntheses, neural protective activities, and inhibition of glycogen synthase kinase-3beta of substituted quinolines.

A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer’s disease mouse model

QCD Strings as Constrained Grassmannian Sigma Model:

We present calculations for the effective action of string world sheet in R3 and R4 utilizing its correspondence with the constrained Grassmannian sigma model. Minimal surfaces describe the dynamics of open strings while harmonic surfaces describe that of closed strings. The one-loop effective action for these are calculated with instanton and anti-instanton background, reprsenting N-string interactions at the tree level. The effective action is found to be the partition function of a classical modified Coulomb gas in the confining phase, with a dynamically generated mass gap.Comment: 22 pages, Preprint: SFU HEP-116-9

Understanding the barriers to integrating maternal and mental health at primary health care in Vietnam

The prevalence of common perinatal mental disorders in Vietnam ranges from 16.9% to 39.9%, and substantial treatment gaps have been identified at all levels. This paper explores constraints to the integration of maternal and mental health services at the primary healthcare level and the implications for the health system’s responsiveness to the needs and expectations of pregnant women with mental health conditions in Vietnam. As part of the RESPONSE project, a three-phased realist evaluation study, we present Phase One findings which employed systematic and scoping literature reviews, and qualitative data collection (focus groups and interviews) with key health system actors, in Bac Giang province, Vietnam, to understand the barriers to maternal mental healthcare provision, utilisation, and integration strategies. A four-level framing of the barriers to integrating perinatal mental health services in Vietnam was used in reporting findings, which comprised individual, socio-cultural, organisational, and structural levels. At the socio-cultural and structural levels, these barriers included: cultural beliefs about the holistic notion of physical and mental health, stigma towards mental health, biomedical approach to healthcare services, absence of comprehensive mental health policy, and a lack of mental health workforce. At the organisational level, there was absence of clinical guidelines on the integration of mental health in routine antenatal visits, a shortage of staff, and poor health facilities. Finally, at the provider level, a lack of knowledge and training on mental health was identified. The integration of mental health into routine antenatal visits at the primary care level has the potential help to reduce stigma towards mental health and improve health system responsiveness by providing services closer to the local level, offering prompt attention, better choice of services, and better communication while ensuring privacy and confidentiality of services. This can improve the demand for mental health services and help reduce the delay of care-seeking

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02